The invention relates to a process for synthesizing piperazic acid and similar, ring-containing acids. The invention also relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of either or both processes in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d).
Piperazic acid derivatives are important intermediates in natural product synthesis and in the synthesis of biologically useful non-natural amino acids and peptidomimetics (e.g., inhibitors described in PCT publications WO 97/22619 and WO 95/35308). Several syntheses of piperazic acid and derivatives thereof have been described [Decicco et al., Syn. Lett., p. 615 (1995); Schmidt et al., Synthesis, p. 223 (1996); Rutjes et al., Tetrahedron, p. 8605 (1993); PCT publications WO 97/22619 and WO 95/35308). In each case however, the synthesis requires multiple steps, utilizes expensive reagents and produces less than desirable yields.
Compounds containing a bicyclic, aza-containing ring systems have been prepared as conformationally restricted dipeptide surrogates for a variety of medically important compounds. In particular, such ring systems are present in angiotensin converting enzyme (ACE) inhibitors, such as Cilazapril(copyright), and in caspase inhibitors, such as inhibitors of interleukin-1 converting enzyme (ICE).
Current methods for synthesizing compounds containing these byciclic aza-containing ring systems have many disadvantages. The typical methods of forming this ring system have been described [EP 94,095, WO 95/35308, WO 97/22619, U.S. Pat. Nos. 5,656,627, 5,716,929 and 5,756,486 and J. P. Kim, et al., Tetrahedron Letters, 38, pp. 4935-4938 (1997)].
These methods involve coupling an appropriately protected amino acid with the appropriately N(1)-protected piperazic acid or ester. After deprotection, the bicyclic system is then formed via an acid chloride coupling at the N(1) position.
The main disadvantages to such methods are the use of expensive reagents and the number of steps required for protection and deprotection making the overall process extremely time consuming. Moreover, these methods are often useful for research purposes but are not amenable to large scale production.
In order to be more commercially feasible, it would be desirable to produce compounds containing a byciclic aza-containing ring system in an easier, less expensive manner than has been previously described.
Applicant has solved the problems indicated above by providing: 1) a new method for synthesizing piperazic acid; and 2) a new method of simultaneously N(2)-acylating an N(1)-protected piperazic acid or an ester thereof and creating a bicyclic ring structure comprising that acylated piperazic acid or ester.
The first method involves treating a 1,4-dihaloalkyl ester with an N,Nxe2x80x2-bis-protected hydrazine dissolved in DMF in the presence of a water scavenger, a metal hydroxide and a phase transfer catalyst. This method produces surprisingly increased yield of the desired protected piperazic acid.
The second method involves the formation of the desired bicyclic system in two, simple steps. This method also utilizes inexpensive reagents, does not require selective protection/deprotection, and is quite amenable to large scale production. Moreover, this method produces very little contaminating by-products. This method also preserves chirality between the N(1)-protected piperazic or similar acid or an ester thereof and the resulting byciclic aza-containing ring system.
This method is particularly useful for producing an intermediate that may be subsequently converted into a caspase inhibitor, particularly an inhibitor of ICE, through additional steps known in the art.
Some of the abbreviations used throughout the specifications (including in chemical formulae) are:   Bu = butyl
Et = ethyl
Cbz = carboxybenzyl
DMF = N,N-dimethylformamide
THF = tetrahydrofuran
MTBE = methyl tert-butyl ether
DCC = dicyclohexyl carbodiimide
EDC  =  1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Ac = acetyl.
According to one embodiment, the invention provides a process for producing compound E by reacting compounds C and D: 
comprising the steps of:
a) dissolving compounds C and D together in DMF;
b) adding to said solution of C and D:
i) a water scavenger;
ii) a metal hydroxide selected from LiOH, NaOH or KOH; and
iii) a phase transfer catalyst
c) allowing the mixture produced in step b) to react at room temperature for 2 to 48 hours;
d) adding an organic solvent and water to said mixture to create an aqueous phase and an organic phase; and
e) purifying compound E from said organic phase;
wherein:
R2 is selected from hydrogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar;
n is 0 or 1;
xe2x80x9cHalxe2x80x9d is any halogen; and
each Rxe2x80x2 is an independently selected carboxyl protecting group
The water scavenger referred to above may be selected from any water scavengers known in the art. These include, but are not limited to, Na2SO4, MgSO4, and molecular sieves. Preferably, the water scavenger is sodium sulfate.
According to another preferred embodiment, the metal hydroxide used in the above method is LiOH.
The phase transfer catalyst referred to in the above method may also be selected from any such catalysts known in the art. These include, but are not limited to, Bu4NI, Aliquat 336 (Aldrich Chemicals) and other quartenary ammonium salts. Preferably, the catalyst is Bu4NI.
According to another preferred embodiment, n is 1 .
According to yet another preferred embodiment, each Hal is Br.
In yet another preferred embodiment of the method set forth above, R2 is t-butyl.
In another preferred embodiment, Rxe2x80x2 is benzyl.
According to another embodiment, the invention provides a process for converting compound G to compound H: 
wherein:
R1 is a C2-C4 straight chain alkyl optionally substituted at any carbon with one or more substituents selected from C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl, Oxe2x80x94C1-C6 straight or branched alkyl, Oxe2x80x94C2-C6 straight or branched alkenyl or alkynyl, oxo, halo, NO2, N(R4) (R4), CN, Ar or Oxe2x80x94Ar;
R2 is selected from hydrogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar;
n is 0 or 1;
Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S;
wherein Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl, Oxe2x80x94C1-C6 straight or branched alkyl, Oxe2x80x94C2-C6 straight or branched alkenyl or alkynyl, oxo, halo, NO2, N(R4) (R4), CN, Ar1, O-Ar1;
wherein
Ar1 is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
each R4 is independently selected from H or an amino protecting group, with the proviso that both R4 are not simultaneously hydrogen.
The term xe2x80x9camino protecting groupxe2x80x9d, as used herein, means a moiety that prevents chemical reactions from occurring on the nitrogen atom to which that protecting group is attached. An amino protecting group must also be removable by a chemical reaction.
In one preferred embodiment, R1 is substituted at the terminal carbon bound to the xe2x80x94COOH moiety with a protected amine. The term xe2x80x9cprotected aminexe2x80x9d as used herein, means a nitrogen-containing moiety which can be chemically modified to an amine.
In another preferred embodiment, R1 is substituted at the other terminal carbon (i.e., the one bound to the ring nitrogen) with oxo, making R1 an acyl-containing moiety. More preferred is when R1 contains both the protected amine substituent and the oxo substituent. One of the most preferred R1 groups is: 
In another preferred embodiment, n is 1.
In yet another preferred embodiment, R2 is t-butyl.
The method of this invention comprises the steps of:
(a) suspending compound G in an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme or CCl4;
(b) adjusting the temperature of the resulting solution to between 20xc2x0 C. and 100xc2x0 C.;
(c) adding base and more than about 1 equivalent of RSOpClp to said solution, wherein R is absent or is selected from C1-C6 straight or branched alkyl or Ar, and each p is independently 1 or 2; and
(d) allowing the reaction to proceed over a period of between 2 and 24 hours. Not all organic solvents may be used to dissolve compound G in step (a). The list of solvents set forth above are known to work. Other similar organic solvents may also work in the reaction and are to be considered part of the present invention. Preferably, the organic solvent is toluene or dichloroethane.
Step (b) is preferably carried out at about 70xc2x0 C.
According to a alternate embodiment, in step (c), less than about 0.2 equivalents of N,N-dimethylformamide may also added.
In another preferred embodiment of step (c), RSOpClp is selected from methanesulfonyl chloride or SOCl2. Preferably, in step (c), about 1 to 3 equivalents of RSOpClp are added.
According to yet another preferred embodiment of step (c), about 2 to 4 equivalents of base are added to the reaction. Preferably, the base is selected from pyridine, collidine, lutidine, NaHCO3, imidazole, triethylamine, N-methylmorpholine, diisopropylethylamine or K2CO3. Most preferably, the base is 2,6-lutidine.
In step (c), the base and the RSOpClp are added simultaneously and may be added all at once to the reaction or gradually over period of time up to 3 hours.
Once the reaction is complete, we prefer to purify compound H by diluting the reaction with an organic solvent and then washing the solution first with NaHCO3 and then with brine. The solution is then dried over Na2SO4 and concentrated.
Compound G may be obtained from compound E. That conversion may be achieved in one of two ways depicted below in Scheme 2, depending upon the nature of R1. 
In Scheme 1, m is 0, 1 or 2; and n, Rxe2x80x2, R1 and R2 are as defined above. Also, in compound F any of the unsubstituted ring carbon atoms may be optionally substituted by one or more substituents independently selected from C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl, Oxe2x80x94C1-C6 straight or branched alkyl, Oxe2x80x94C2-C6 straight or branched alkenyl or alkynyl, oxo, NO2, N(R4) (R4), CN, Ar, or O-Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar, and wherein R4 and Ar are as defined above.
Reaction 4A comprises stepwise deprotection and acylation (which can be performed in the same reaction vessel) if the carboxyl protecting groups can be removed by hydrogenolysis, (e.g., if the protecting group is benzyl) or utilizing transfer hydrogenation conditions. If not, a deprotection step must precede the addition of the anhydride for the acylation reaction.
In order to completely deprotect at both nitrogens under transfer hydrogenation conditions, at least 2 equivalents of the proton donor (e.g., Et3SiH) must be added. If only one equivalent of the proton donor is added, deprotection occurs selectively at the N(2) nitrogen: 
The resulting N(1) protected compound is also useful as an intermediate in producing medically important compounds, such as the ICE inhibitors described herein and in PCT publications WO 97/22619 and WO 95/35308. Thus, this reaction to produce an N(1) protected compound is also an embodiment of the present invention.
When compound F contains substituents and is not symmetrical, reaction 4A produces mixtures of compounds, wherein acylation of the N(1) nitrogen may occur at either C(O) functionality. This may be avoided by using substituents that favor the formation of the desired product. For example, in reaction 4A, the use of: 
as compound F forces the formation of a compound wherein acylation of the N(1) nitrogen occurs at the C(O) functionality furthest away from the pthalimide substituent.
In order to avoid an unwanted reaction at the N(2) nitrogen in step 4B, the two carboxy protecting groups (Rxe2x80x2) on compound E should be different, such that the N(1) protecting group (xe2x80x94COORxe2x80x2) can be selectively removed without removing the N(2) protecting group.
The creation of intermediate E can be achieved by standard syntheses known in the art. More preferably, intermediate E is synthesized by reacting compounds C and D according to the method of this invention as set forth above.
Intermediate compound G containing the protected amine on R1, and its subsequent conversion to compound H, may serve as the key intermediate and synthesis step, respectively, in an improvement in the synthesis of known caspase inhibitors, particularly inhibitors of interleukin-1 converting enzyme (xe2x80x9cICExe2x80x9d), such as those described in U.S. Pat. Nos. 5,716,929, 5,656,627, and 5,756,466 and in PCT publications WO 95/35308 and WO 97/22619.
Those inhibitors have the general formula (I): 
wherein:
any ring is optionally substituted at any carbon by Q1, at any nitrogen by R5, and at any atom by xe2x95x90O, xe2x80x94OH, xe2x80x94COOH, or halogen;
X1 is CH or N;
g is 0 or 1;
m and mxe2x80x2 are independently 0, 1 or 2;
n is 0 or 1;
each J is independently selected from xe2x80x94H, xe2x80x94OH, or xe2x80x94F, provided that when a first and a second J are bound to a C, and said first J is xe2x80x94OH, then said second J is xe2x80x94H;
T is -Ar3, xe2x80x94OH, xe2x80x94CF3, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94OH, xe2x80x94C(O)xe2x80x94OH or any biosteric replacement for xe2x80x94C(O)xe2x80x94OH;
R3 is xe2x80x94CN, xe2x80x94CHxe2x95x90CHxe2x80x94R9, CHxe2x95x90Nxe2x80x94Oxe2x80x94R9, xe2x80x94(CH2)1-3-T1-R9, xe2x80x94CJ2-R9, xe2x80x94C(O)xe2x80x94R13, or xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(R5) (R10)
T1 is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x940xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR10xe2x80x94, Oxe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)Oxe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94S(O)2xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94S(O)2xe2x80x94 or xe2x80x94NR10xe2x80x94S(O)2xe2x80x94NR10xe2x80x94;
each R5 is independently selected from xe2x80x94H, -Ar1, xe2x80x94C(O)-Ar1, xe2x80x94S(O)2-Ar1, xe2x80x94R9, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94S(O)2xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O)xe2x80x94Oxe2x80x94R9, xe2x80x94S(O)2xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R10) (Ar1), xe2x80x94S(O)2xe2x80x94N(R10) (Ar1) , xe2x80x94C(O)xe2x80x94N(R10) (R9) , or xe2x80x94S(O)2xe2x80x94N(R10) (R9); each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted with xe2x80x94OH, xe2x80x94F, xe2x95x90O or Ar1, wherein any R9 may be substituted with a maximum of two Ar1;
each R10 is independently selected from xe2x80x94H or C1-6 straight or branched alkyl;
R13 is xe2x80x94H, -Ar1, xe2x80x94R9, -T1-R9 or xe2x80x94(CH2)1-3-T1-R9;
each Ar1 is a cyclic group independently selected from a monocyclic, bicyclic or tricyclic aryl group containing 6, 10, 12 or 14 carbon atoms; a monocyclic, bicyclic or tricyclic cycloalkyl group containing between 3 and 15 carbon atoms, said cycloalkyl group being optionally benzofused; or a monocyclic, bicyclic or tricyclic heterocycle group containing between 5 and 15 ring atoms and at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94, wherein said heterocycle group optionally contains one or more double bonds and optionally comprises one or more aromatic rings;
Ar3 is a cyclic group selected from phenyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, wherein said heteroaromatic rings comprise from 1-3 heteroatom groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94;
wherein each Ar1 or Ar3 is optionally singly or multiply substituted at any ring atom by xe2x80x94NH2, xe2x80x94C(O)xe2x80x94OH, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
or -Q1; and
each Q1 is independently selected from -Ar1, xe2x80x94R9, -T1-R9, or (CH2)1-3-T1-R9; provided that when -Ar1 is substituted with a Q1 which comprises one or more additional -Ar1 groups, said additional -Ar1 groups are not substituted with Q1.
Preferably, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein n is 1 and m is 2.
In another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein R5 is an acyl moiety selected from xe2x80x94C(O)-Ar1, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O)xe2x80x94Oxe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R10) (Ar1), or xe2x80x94C(O)xe2x80x94N(R10) (R9).
In yet another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein X1 is CH; each J is H; mxe2x80x2 is 1; T is xe2x80x94COOH or a biosteric replacement for xe2x80x94COOH; g is 0; and R3 is xe2x80x94C(O)xe2x80x94R13.
In the most preferred embodiment of using the process of this invention as a step in the synthesis of a compound of formula I, said compound has the structure: 
Alternatively, the process of this invention may be used as a step in the synthesis of a compound of the formula (II): 
wherein:
Z is selected from 
p is 1 or 2 ;
each R5, is independently selected from xe2x80x94C(O)xe2x80x94R10, xe2x80x94C(O)Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(R10xe2x80x2) (R10xe2x80x2), xe2x80x94S(O)2xe2x80x94R9xe2x80x2, xe2x80x94S(O)2xe2x80x94NHxe2x80x94R10xe2x80x2, xe2x80x94C(O)xe2x80x94CH2xe2x80x94Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94R9xe2x80x2, xe2x80x94H, xe2x80x94C(O)C(O) xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N(R9xe2x80x2) (R10xe2x80x2);
each R9xe2x80x2, is independently selected from -Ar1 or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar1, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
each R10xe2x80x2 is independently selected from xe2x80x94H, -Ar1, a xe2x80x94C3-6 cycloalkyl group, or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar3xe2x80x2, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
R13xe2x80x2 is selected from H, Ar1, or a C1-6 straight or branched alkyl group optionally substituted with Ar1, xe2x80x94CONH2, xe2x80x94OR5xe2x80x2, xe2x80x94OH, xe2x80x94OR9xe2x80x2, or xe2x80x94CO2H;
each R51 is independently selected from R9xe2x80x2, xe2x80x94C(O)xe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(H)xe2x80x94R9xe2x80x2, or two R51 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
each R21 is independently selected from xe2x80x94H or a xe2x80x94C1-6 straight or branched alkyl group;
Y2 is xe2x80x94H2 or xe2x95x90O
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, SO2, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -Q1;
each Q1 is independently selected from the group consisting of xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, R5xe2x80x2, xe2x80x94OR5xe2x80x2, xe2x80x94NHR5xe2x80x2, OR9xe2x80x2, xe2x80x94N(R9xe2x80x2) (R10xe2x80x2) R9xe2x80x2, xe2x80x94C(O)xe2x80x94R10xe2x80x2, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional -Ar1 groups, said additional -Ar1 groups are not substituted with another -Ar1.
Preferably, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein Y2 is O and R21 is H.
In another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein R5xe2x80x2, is selected from xe2x80x94C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(R10xe2x80x2) (R10xe2x80x2), xe2x80x94C(O)xe2x80x94CH2xe2x80x94Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N(R9xe2x80x2) (R10xe2x80x2).
In yet another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein Z is 
p is 1 and R51 is selected from -Ar1, xe2x80x94C1-6 straight or branched alkyl or xe2x80x94C1-6 straight or branched alkyl substituted with Ar1.
In the most preferred embodiment of using the process of this invention as a step in the synthesis of a compound of formula II, said compound has the structure: 
In the synthesis of these inhibitors, the terminal carbon of R1 adjacent the xe2x80x94COOH moiety contains a protecting substituent. Preferably that protecting substituent is 
The synthesis steps from compound H to the inhibitors set forth above involve removal of the protecting substituent on R1; coupling of the R5xe2x80x94NHxe2x80x94 or R5xe2x80x2xe2x80x94NHxe2x80x94 moiety in its place; hydrolysis of the R2 group; and coupling of the amine 
in its place.
The removal of the protecting substituent on R1 is typically carried out with hydrazine. The subsequent coupling of the resulting amine to form the R5xe2x80x94NHxe2x80x94 or R5xe2x80x2xe2x80x94NHxe2x80x94 moiety is achieved with standard coupling reagents, such as EDC, DCC or acid chloride.
Depending upon the nature of R2, its hydrolysis may be achieved with an acid (when R2 is t-butyl), a hydroxide (when R2 is any other alkyl, alkenyl or alkynyl or Ar) or hydrogenolysis (when R2 is an Ar-substituted alkyl, alkenyl or alkynyl). This produces the corresponding acid from the ester.
The acid is then coupled to the amine with standard coupling reagents, such as EDC, DCC or acid chloride.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.